P1024: MYLOX-1: A PHASE II STUDY EVALUATING THE SAFETY, TOLERABILITY, PHARMACOKINETICS AND PHARMACODYNAMICS OF ORAL LOXL2 INHIBITOR GB2064 (WITH FOCUS ON BONE MARROW COLLAGEN) IN PATIENTS WITH MYELOFIBROSIS
Authors: Claire Harrison, John Mascarenhas, Daniela Cilloni, Richard Schlenk, Brian Jacoby, Robert J Slack, Vassilios Aslanis, Bhupinder Singh, Bertil Lindmark, Srdan Verstovsek, Raajit K Rampal
Journal: HemaSphere (2023)

Topic: 16. Myeloproliferative neoplasms - Clinical Background: Myelofibrosis (MF) treatment (Tx) with Janus kinase (JAK) inhibitors is limited by modest effects on bone marrow (BM) fibrosis & driver mutation allele burden. A high proportion of patients (pts) discontinue Tx due to cytopenias. GB2064, a LOXL2 inhibitor, is being developed as a potential disease-modifying Tx for MF. Aims: To evaluate safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) & clinical effects, specifically potential effects on BM collagen fibrosis, of oral GB2064 in pts with primary or secondary MF (PMF/SMF). Methods: MYLOX-1 (NCT04679870) is a phase II trial of oral GB2064 (1000 mg BID) administered in pts with PMF/SMF for 9 months, with follow-up 1 month after their last dose. Eligible pts were not allowed JAK inhibitors, had clinical laboratory parameters within protocol-defined limits & an ECOG performance status of 0–2. Primary endpoints: Safety & tolerability. Clinical visits occurred at protocol-specified timepoints: safety & tolerability, PK, PD & appropriate MF-specific assessments occurred at all visits except on Day (D) 7, D15 & Month (M) 4, when only safety & tolerability were assessed. BM biopsies & MRI of the spleen were performed at baseline & M3, M6 & M9. Pts who showed clinical benefit entered an extension phase & may continue Tx for an additional 3 years, during which only safety & tolerability are assessed. Results: As of early February 2023, 17 pts have been enrolled & started Tx (59% PMF); 10 JAK2 positive (3 with co-existing ASXL1 mutations, 1 with co-existing MPL & ASXL1 mutations), 2 MPL positive, 4 CALR positive (1 with co-existing EZH2 mutation) & 1 ASXL1 positive. JAK2 inhibitor status: 4 refractory, 8 intolerant, 2 ineligible, 3 naïve. Dynamic International Prognostic Scoring System plus risk distribution: High for 2 pts, Intermediate-2 for 8, Intermediate-1 for 5 & Low for 2. Overall, 6 pts have completed Tx (2 are in the extension phase), 10 have discontinued Tx (6 due to adverse events [AEs], 3 due to disease progression) & 1 is continuing Tx. At the safety data cut-off (6 October 2022), all pts who received GB2064 experienced Tx-emergent AEs. Most were gastrointestinal in nature (11/16 pts), including nausea (6/16 pts) & vomiting (3/16 pts), & were either self-limiting or responded to anti-emetics. Serious AEs were experienced by 7 pts, 1 was Tx related (fall). Of 5 evaluable pts who received GB2064 for >6 months & had complete BM biopsy data, 1 (20%) showed improved ≥1-grade reticulin fibrosis, & 4 (80%) experienced a 1- or 2 grade reduction in collagen fibrosis (Figure). Spleen volume & hematological parameters remained stable from baseline to M6 for the 4 pts with BM collagen fibrosis response; none required transfusion. After M6 assessments, 2/4 pts progressed to the extension phase due to clinical benefit seen with GB2064 (1 experienced a total symptom score reduction >50% & the other an Anemia response). BM penetration by GB2064 was demonstrated through spatial distribution in M3 BM biopsies using matrix-assisted laser desorption/ionization mass spectrometry imaging. GB2064 showed good target engagement in plasma, with a 49.5% decrease in free LOXL2 from baseline to 2 hours post-dosing. Summary/Conclusion: Pts with MF who received GB2064 had an acceptable safety profile & improvements in BM reticulin & collagen fibrosis that indicated disease-modifying activity. GB2064 demonstrated BM penetration & good target engagement in plasma, thus may be a valid Tx option or disease-modifying combination agent for pts ineligible or intolerant to JAK inhibitors, or in combination with JAK inhibitors & novel therapies. Figure:Keywords: Clinical trial, Bone Marrow Fibrosis, Myelofibrosis, Janus Kinase inhibitor